Shock is a life-threatening complication in situations associated with trauma including burns, surgery, ischemia, sepsis, and other critical care applications. Shock is a broad term that describes a group of circulatory syndromes, all of which result in general cellular hypoxia, and ultimately lead to irreversible cardiovascular collapse because of their combined effects on the microcirculation.
Shock is a multifaceted systemic response to any of a number of stress inducing stimuli that results in cellular activation and release of a number of interacting response mediators, including cytokines, inflammatory and immune mediators, and nitric oxide (NO). During an immune response, oxygen free radicals and superoxides are generated to kill pathogens. However, oxygen free radicals and superoxides are also damaging to the host cells, resulting in oxidation of lipids, proteins and nucleic acids. The mediators of shock orchestrate complex biological interactions and amplification of signals that result in a systemic response to a localized insult.
Due to the multifaceted nature of factors inducing shock, development of therapeutics has been difficult. Most therapies have focused on the modulation of a single factor (e.g. cytokines, NO, endotoxin) to mitigate the effects of shock. Unfortunately, inhibition of any one of these pleiotropic factors is ineffective. Organ specific therapies can support life, but are not an ideal option as they often sacrifice remote organ function.
One potential therapeutic molecule that has been suggested for use in shock is the bactericidal/permeability-increasing protein (BPI), a protein involved in the immune response (Ammons, U.S. Pat. No. 6,017,881). Intestinal ischemia, frequently associated with shock, results in the breakdown of the intestinal mucosal permeability barrier allowing for the translocation of bacteria and/or endotoxin from the intestinal lumen to the vascular system. During shock, endotoxin has been detected in the portal vein, but its role in shock has not been clearly defined. BPI is a protein typically isolated from granules of mammalian polymorphonuclear cells (PMNs). PMNs are blood cells involved in the defense of the body against invading microorganisms. BPI is highly specific for gram negative bacteria and seems to have no deleterious effects on other pathogens or host cells. Administration of BPI to rats results in a decrease in the adverse physiological effects of intestinal ischemia which may catalyze the other symptoms of shock. However BPI only affects one of the pathways that are activated in shock, so it is of limited use. Additionally, BPI acts by attacking the endotoxin and bacteria after they have been released from the intestine into the bloodstream; therefore, it cannot be used to prevent the occurrence shock.
In another approach, the inventors demonstrated the role of pancreatic proteases in shock and protective effects of certain uses of protease inhibitors as described in U.S. Pat. No. 6,534,283. Pancreatic enzymes are released normally into the small intestine for digestion with no adverse effects. However, during shock, the intestinal permeability barrier is compromised, and the inventors therefore theorized that protease susceptible sites not present under normal conditions are revealed, tissues are broken down, and proteolytic products that are strong activators of shock are released. A variety of so formed proteolytic products can act as mediators of shock, and the inventors consequently considered that shock is most effectively treated by preventing in the small intestine protease activation or by the inhibition or elimination of the proteases in the small intestine that generate the activators of shock. To that end, the inventors believed that administration of protease inhibitors directly into the small intestine would prevent shock in rats as determined by both survival time and molecular and histological analysis.
However, while experimental observations seemed to confirm at least certain effects of protease inhibitors (e.g., inhibition of the activation of circulating neutrophils, attenuated myeloperoxidase activity), the inventors only considered possible prophylactic intervention using administration of protease inhibitors directly to the small intestine.
Thus, even though there are various methods for treatment or prophylaxis of shock known in the art, there is still a need to provide effective methods and compositions for treatment of shock and shock associated conditions.